August 13, 2018
2 min read

SGLT-2 inhibitors may increase risk for amputation in type 2 diabetes

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New users of sodium-glucose cotransporter 2 inhibitors may be more likely to undergo a lower extremity amputation when compared with users of other treatments for type 2 diabetes, such as sulfonylureas, metformin and thiazolidinediones, according to data published in JAMA Internal Medicine.

“Results of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation,” Hsien-Yen Chang, PhD, from the Center for Drug Safety and Effectiveness at Johns Hopkins Bloomberg School of Public Health, and colleagues wrote.

“Because all SGLT-2 inhibitors share similar mechanisms of action, a warning for amputations as a class effect was applied to all SGLT-2 inhibitors after review of clinical trial data,” they added. “Our study supplements this body of evidence by investigating the risk of lower extremity amputations across three SGLT-2 inhibitors and including a variety of additional outcomes of interest to patients, clinicians, and regulators.”

The FDA has approved two more SGLT-2 inhibitors, dapagliflozin and empagliflozin, since its approval of canagliflozin, but their influence on amputations are unknown, according to the researchers.

Chang and colleagues conducted a retrospective cohort study to investigate the effects of all three SGLT-2 inhibitors on lower extremity amputation, peripheral arterial disease, osteomyelitis and venous ulceration among patients with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists and other antidiabetic agents, including sulfonylurea, metformin hydrochloride and thiazolidinediones.

The researchers studied 953,906 patients (mean age, 51.8 years); of whom 4.2% (n = 39,869) were new users of SGLT-2 inhibitors, 11% (n = 105,023) were new users of DPP-4 inhibitors and 4.1% (n = 39,120) were new users of GLP-1 agonists. They observed participants for a median range of 99 days to 127 days.

Lower extremity amputations were rare, with crude incident rates ranging from 4.9 per 10,000 person-years for patients using metformin, sulfonylureas and thiazolidinediones to 10.53 per 10,000 person-years for new users of SGLT-2 inhibitors.

Data showed that new users of SGLT-2 inhibitors had a higher risk of amputation than new users of DPP-4 inhibitors (adjusted HR = 1.5; 95% CI, 0.85-2.67) and GLP-1 agonists (aHR = 1.47; 95% CI, 0.64-3.36) after propensity score weighting and adjusting for demographics, severity of diabetes, comorbidities and medications.

Conversely, new users of SGLT-2 inhibitors had a significant risk for amputation compared with sulfonylureas, metformin or thiazolidinediones (aHR = 2.12; 95% CI, 1.19-3.77). Results remained consistent in sensitivity analyses.


“Given the uncertainty regarding the true nature of the association between SLGT-2 inhibitors and amputation, clinicians and patients will have to navigate treatment choices while balancing the potential risks of these products against their benefits and alternatives,” Chang and colleagues concluded.

“As the regulatory communications from the FDA and European Medicines Agency make clear, there is a pressing need for further information derived from a number of sources, ranging from passive surveillance systems to meta-analyses of large studies, including observational studies of vascular outcomes such as those we examine herein,” they added. – by Alaina Tedesco

Disclosure: Chang reports no relevant financial disclosures. Please see study for all other authors’ relevant financial disclosures.